Successful Intervention in an Initially Asymptomatic Patient Who Was Diagnosed With Pulmonary Alveolar Proteinosis Due to MARS1 Mutation

Abstract Introduction: Protein alveolar proteinosis (PAP) typically presents with respiratory distress and hypoxemia. We describe a patient with PAP secondary to a MARS1 mutation, initially asymptomatic from a respiratory perspective who subsequently developed hypoxemia and was successfully treated with methionine and serial whole lung lavages. Case Description: Patient presented at 12 months of age with failure to thrive, mild hypotonia and developmental delay. His care was complicated by his recent arrival from a tuberculosis (TB)-endemic country. He had no respiratory findings with normal oxygen saturations. His initial chest x-ray showed diffuse reticulonodular changes (Fig 1a) and he was started on tuberculosis treatment (TB investigations subsequently negative) Respiratory Medicine assessed at 18 months of age for a worsening TB surveillance x-ray (Figure 1b) although he still had no respiratory signs or symptoms. A subsequent CT scan (Figure 1c) and bronchoscopy confirmed diagnosis of pulmonary alveolar proteinosis (PAP). Whole exome sequencing identified a homozygous variant of uncertain significance in MARS1 ((NM_004990.3):c.854T>C, p.Ile285Thr), which had been reported in another case of neonatal PAP. At 20 months of age, he was admitted with parainfluenza 3, respiratory distress, hypoxemia, failure to thrive and persistent vomiting. Oral methionine was initiated with target pre-dose level of 45-60 μmol/L and post-dose level not to exceed 400-500 μmol/L, but two months later he still required oxygen support via high-flow nasal cannulae. He underwent bilateral whole lung lavage (WLL), and was weaned to low flow oxygen 6 days later. His oxygen requirement increased 3 weeks later and had a second WLL 42 days after the first, leading to modest clinical improvement. He was discharged on home oxygen and GJ tube feeds. Two months later he was admitted with entero/rhinovirus infection and couldn't wean back to his previous oxygen level. A third bilateral WLL was performed, and he subsequently came off low flow oxygen 4 months later. He remains asymptomatic 1 year after his last WLL although still requires GJ tube feeds and has persisting abnormalities on his chest CT (Fig 1d). Importance of this case: This case illustrates the importance of considering PAP as a cause of diffusely abnormal chest imaging in patients who don't have respiratory symptoms, as imaging changes can precede clinical findings. This adds to the growing body of literature describing successful treatment of MARS1-related PAP with methionine. As reported previously, WLL may be needed initially as an adjunctive treatment and to maximize the effect of methionine.

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